STAT5A Regulates the Survival of Mammary Epithelial Cells and the Development of Mammary Cancer
Abstract
The in vivo relationship between epidermal growth factor (EGF) and prolactin/Jak/Stat signaling pathways in mammary gland development and tumorigenesis was explored in transgenic nice overexpressing the TGF alpha gene (TGFalphaTG) and lacking the prolactin-activated transcription factor, Stat5a (Stat5aKO/TGFalphaTG). We present evidence that Stat5a has a crucial role regulating programmed cell death (PCD) during mammary gland involution and the development of EGF-dependent tumorigenesis. TGFaalphaTG mice exhibit delayed mammary gland involution and the absence of Stat5a facilitated involution-associated changes in morphology and the extent and timing of PCD. Stat5a remained phosphorylated through involution in TGFalphaTG suggesting that Stat5a is constituitively 'activated' by the EGF signaling pathway. These results demonstrated TGFalpha epithelium is prevented from progressing into the normal pattern of involution and apoptosis by the 'activated' form of Stat5a. This activated Stat5a affected EGF-receptor initiated mammary gland tumorigenesis. Overexpression of TGFalpha in mammary epithelium generates mammary hyperplasia and tumors. In the presence of an activated EGF receptor, deletion of Stat5a delayed initial hyperplasia and mammary tumor development by 6 weeks. These observations demonstrate that Stat5a is a survival factor, is required for mammary gland epithelium to resist regression and involution-mediated apoptosis and can influence the development of mammary gland tumorigenesis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA385738
Entities
People
- Robin Humphreys
Organizations
- National Institutes of Health